Comparison of human skin irritation patch test data with in vitro skin irritation assays and animal data.

BACKGROUND: Efforts to replace the rabbit skin irritation test have been underway for many years, encouraged by the EU Cosmetics Directive and REACH. Recently various in vitro tests have been developed, evaluated and validated. OBJECTIVE: A key difficulty in confirming the validity of in vitro methods is that animal data are scarce and of limited utility for prediction of human effects, which adversely impacts their acceptance. This study examines whether in vivo or in vitro data most accurately predicted human effects. METHODS: Using the 4-hr human patch test (HPT) we examined a number of chemicals whose EU classification of skin irritancy is known to be borderline, or where in vitro methods provided conflicting results. RESULTS: Of the 16 chemicals classified as irritants in the rabbit, only five substances were found to be significantly irritating to human skin. Concordance of the rabbit test with the 4-hr HPT was only 56%, whereas concordance of human epidermis models with human data was 76% (EpiDerm) and 70% (EPISKIN). CONCLUSIONS: The results confirm observations that rabbits overpredict skin effects in humans. Therefore, when validating in vitro methods, all available information, including human data, should be taken into account before making conclusions about their predictive capacity.

The effect of population diversity on skin irritation.

The impact of many human variables on the response to skin irritating substances has been studied to varying degrees, including the impact of age, sex, and atopic status. However, the importance of ethnic origin has been more difficult to investigate, leading to a relative paucity of compelling data, either for or against the existence of differences. A primary reason for this lack is that studies on different ethnic groups often have to be undertaken in different locations thus introducing variables, e.g. time, environmental conditions that confound interpretations. In the present work, an attempt has been made to eliminate all variables except ethnicity by conducting a study on 2 distinct populations (Punjabis and Tamils) at the same location on the same day with a single assessor of the skin reactions, using sodium lauryl sulfate as the skin irritant. The skin reactions were assessed visually, and it was demonstrated that the modality of the reactions in these 2 populations had clear differences, but that the dose-response profiles were very similar. Thus, although the irritant response was expressed differently (e.g. erythema was much less evident in the darker Tamil population), the overall outcome was that the populations reacted in an equivalent manner.

The complex problem of sensitive skin.

There exists within the population subsets of individuals who display heightened skin reactivity to materials the majority find tolerable. In a series of investigations, we have examined interrelationships between many of the endpoints associated with the term 'sensitive skin'. In the most recent work, 58 volunteers were treated with 10% lactic acid, 50% ethanol, 0.5% menthol and 1.0% capsaicin on the nasolabial fold, unoccluded, with sensory reactions recorded at 2.5 min, 5 min and 8 min after application. Urticant susceptibility was evaluated with 1 m benzoic acid and 125 mM trans-cinnamic acid applied to the volar forearm for 20 min. A 2 x 23-h patch test was also conducted using 0.1% and 0.3% sodium dodecyl sulfate, 0.3% and 0.6% cocamidopropyl betaine and 0.1% and 0.2% benzalkonium chloride to determine irritant susceptibility. As found in previous studies, increased susceptibility to one endpoint was not predictive of sensitivity to another. In our experience, nasolabial stinging was a poor predictor of general skin sensitivity. Nevertheless, it may be possible to identify in the normal population individuals who, coincidentally, are more generally sensitive to a range of non-immunologic adverse skin reactions. Whether such individuals are those who experience problems with skin care products remains to be addressed.

Strong irritants masquerading as skin allergens: the case of benzalkonium chloride.

Chemicals may possess a number of hazards to human health including the ability to cause skin irritation and contact allergy. Identification and characterization of these properties should fall within predictive toxicology, but information derived from human exposure, including clinical experience, is also of importance. In this context, it is of interest to review the case of benzalkonium chloride, a cationic surfactant. This chemical is a well-known skin irritant, but on occasions it has also been reported to have allergenic properties, typically on the basis of positive diagnostic patch test data. Because the accumulated knowledge concerning the properties of a chemical is employed as the basis for its regulatory classification (e.g. in Europe), as well as for informing the clinical community with respect to the diagnosis of irritant versus allergic contact dermatitis (ACD), it is important to distinguish properly which chemicals are simply irritants from those which are both irritant and allergenic on skin. A review of the information on benzalkonium chloride confirms that it is a significant skin irritant. However, both predictive test results and clinical data lead to the conclusion that benzalkonium chloride is, at most, an extremely rare allergen, except perhaps in the eye, but with many supposed cases of ACD being likely to arise from the misinterpretation of patch test data. As a consequence, this substance should not normally be regarded as, or classified as, a significant skin sensitizer.

Facial variations in sensory responses.

Subjective effects such as stinging, itching and burning commonly occur in the absence of any visible irritation and give rise to discomfort, which may be enough to deter an individual from using even the most effective of skin care products. The purpose of this study was to evaluate the sensitivity of different anatomical regions of the face to determine which region displayed the most intense stinging response to the application of lactic acid. The effect of occlusion on the level of response was also investigated. 45 volunteers were treated with 10% lactic acid on the nasolabial fold, forehead, chin and cheek, occluded and unoccluded for 8 min. Sensory reactions were recorded at 2.5, 5 and 8 min. The response levels on the occluded sites were always significantly lower than on the unoccluded sites, despite the dose per unit area being comparable. Females showed a trend towards being more sensitive to the subjective effects elicited by lactic acid than males, but these results were not conclusive. Interestingly, there was not a complete correlation between individuals who reacted on the nasolabial fold and the other sites, particularly the forehead. A positive stinging response on the nasolabial fold may not necessarily predict subjective responses to a product when used on other areas of the face.